MVK – Mevalonic aciduria

Mevalonic aciduria is a rare autosomal recessive metabolic disorder characterized by early-onset psychomotor retardation, failure to thrive (HP:0001508), hepatosplenomegaly (HP:0001433), anemia (HP:0001903), and recurrent febrile crises. The disease is caused by biallelic loss-of-function variants in MVK, encoding mevalonate kinase, which catalyzes the phosphorylation of mevalonate in the isoprenoid biosynthesis pathway.

Genetic evidence for MVK-related mevalonic aciduria includes at least 30 unrelated probands from multiple families with recessive segregation of pathogenic variants across cohorts (PMID:10401001, PMID:16835861, PMID:34145613). Variant spectrum encompasses over 63 distinct MVK mutations, including missense (e.g., c.803T>C (p.Ile268Thr)), nonsense, splice-site, and frameshift alleles. Segregation of compound heterozygous or homozygous genotypes correlates with disease severity, with the homozygous p.Ile268Thr genotype linked to classic severe presentation (PMID:22271696).

Functional assays demonstrate profound loss of mevalonate kinase activity and protein stability for MVK variants. Heterologous expression of mutant enzymes in Escherichia coli and immunoblot analysis of patient fibroblasts reveal negligible enzyme levels and activity (PMID:10401001). Sensitive UPLC-MS/MS quantification of mevalonate-5-phosphate confirms <0.5% residual activity in severe cases, and accumulation of unprenylated Rab and Rap1A in PBMCs serves as a biomarker distinguishing MVK deficiency (PMID:31474985). Transcriptome profiling in patient fibroblasts at elevated temperature uncovers dysregulation of cell cycle and cytoskeletal genes due to ectopic activation of Rho GTPases (PMID:38636615).

Mechanistically, MVK loss-of-function leads to impaired isoprenoid synthesis, defective prenylation of small GTPases, and downstream cellular dysfunction including autophagy impairment and apoptosis in neuronal models. The degree of residual enzyme activity inversely correlates with prenylation defects and clinical severity, supporting a graded dysfunction model.

No studies have robustly refuted the MVK–mevalonic aciduria association. Collectively, strong genetic and orthogonal functional evidence support a definitive gene–disease relationship. Biallelic MVK variants should be included in diagnostic panels for suspected mevalonic aciduria and can inform therapeutic strategies such as isoprenoid pathway modulation.

Key take-home: Biallelic MVK loss-of-function variants definitively cause autosomal recessive mevalonic aciduria, with robust genetic segregation and functional data underpinning clinical diagnostic and therapeutic decision-making.

References

• Human molecular genetics • 1999 • Identification and characterization of three novel missense mutations in mevalonate kinase cDNA causing mevalonic aciduria, a disorder of isoprene biosynthesis. PMID:10401001
• Human mutation • 2006 • Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. PMID:16835861
• Journal of inherited metabolic disease • 2021 • Phenotypic diversity, disease progression, and pathogenicity of MVK missense variants in mevalonic aciduria. PMID:34145613
• Pediatrics • 2012 • Clinical, genetic, and therapeutic diversity in 2 patients with severe mevalonate kinase deficiency. PMID:22271696
• Frontiers in immunology • 2019 • Defective Protein Prenylation in a Spectrum of Patients With Mevalonate Kinase Deficiency. PMID:31474985
• Biochimica et biophysica acta. Molecular basis of disease • 2024 • Molecular and cellular consequences of mevalonate kinase deficiency. PMID:38636615

Evidence Based Scoring (AI generated)